Issue 44, 2017

On the selectivity of the NaChBac channel: an integrated computational and experimental analysis of sodium and calcium permeation

Abstract

Ion channel selectivity is essential for their function, yet the molecular basis of a channel's ability to select between ions is still rather controversial. In this work, using a combination of molecular dynamics simulations and electrophysiological current measurements we analyze the ability of the NaChBac channel to discriminate between calcium and sodium. Our simulations show that a single calcium ion can access the Selectivity Filter (SF) interacting so strongly with the glutamate ring so as to remain blocked inside. This is consistent with the tiny calcium currents recorded in our patch-clamp experiments. Two reasons explain this scenario. The first is the higher free energy of ion/SF binding of Ca2+ with respect to Na+. The second is the strong electrostatic repulsion exerted by the resident ion that turns back a second potentially incoming Ca2+, preventing the knock-on permeation mechanism. Finally, we analyzed the possibility of the Anomalous Mole Fraction Effect (AMFE), i.e. the ability of micromolar Ca2+ concentrations to block Na+ currents. Current measurements in Na+/Ca2+ mixed solutions excluded the AMFE, in agreement with metadynamics simulations showing the ability of a sodium ion to by-pass and partially displace the resident calcium. Our work supports a new scenario for Na+/Ca2+ selectivity in the bacterial sodium channel, challenging the traditional notion of an exclusion mechanism strictly confining Ca2+ ions outside the channel.

Graphical abstract: On the selectivity of the NaChBac channel: an integrated computational and experimental analysis of sodium and calcium permeation

Supplementary files

Article information

Article type
Paper
Submitted
30 Aug 2017
Accepted
09 Oct 2017
First published
01 Nov 2017
This article is Open Access
Creative Commons BY license

Phys. Chem. Chem. Phys., 2017,19, 29840-29854

On the selectivity of the NaChBac channel: an integrated computational and experimental analysis of sodium and calcium permeation

C. Guardiani, O. A. Fedorenko, S. K. Roberts and I. A. Khovanov, Phys. Chem. Chem. Phys., 2017, 19, 29840 DOI: 10.1039/C7CP05928K

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